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Title: Midcourse correction to a clinical trial when the event rate is underestimated: The Look AHEAD (Action of health in diabetes) study

Author
item BRANCATI, FREDERICK - Johns Hopkins University
item EVANS, MARY - National Institute Of Diabetes And Digestive And Kidney Diseases
item FURBERG, CURT - Wake Forest University
item GELLER, NANCY - National Heart, Lung And Blood Institute(NHLBI, NIH)
item HAFFNER, STEVEN - University Of Texas Health Science Center
item KAHN, STEVEN - Veterans Administration, Puget Sound Health Care System
item KAUFMANN, PETER - National Heart, Lung And Blood Institute(NHLBI, NIH)
item LEWIS, CORA - University Of Alabama
item NATHAN, DAVID - Massachusetts General Hospital
item PITT, BERTRAM - University Of Michigan
item SAFFORD, MONIKA - University Of Alabama
item FOREYT, JOHN - Children'S Nutrition Research Center (CNRC)

Submitted to: Clinical Trials
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2012
Publication Date: 2/1/2012
Citation: Brancati, F.L., Evans, M., Furberg, C.D., Geller, N., Haffner, S., Kahn, S.E., Kaufmann, P.G., Lewis, C.E., Nathan, D.M., Pitt, B., Safford, M.M., Foreyt, J.P., Look AHEAD Research Group. 2012. Midcourse correction to a clinical trial when the event rate is underestimated: The Look AHEAD (Action of health in diabetes) study. Clinical Trials. 9(1):113-124.

Interpretive Summary: The Look AHEAD study is a long-term clinical study designed to see the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention in obese adults with type 2 diabetes. The goal of this study was to have an 18% decrease in rate of cardiovascular events over the 10.5-year study and follow-up. However, the rate of decrease in CVD events was lower than expected after the first 2 years. Eventually, the portions of the design were modified under recommendations from a review board. These changes included: altering the desired endpoint of the study (the desired reduction of CVD events) and extending the follow-up time of subjects to ensure that any changes in the rate of CVD events can be monitored. Every study has errors that may only become apparent after trials and subjects have already been tested. It is important to recognize such errors and make modifications to the desired endpoints of a study as they become apparent, rather than continue research with inaccurate data and goals. As issues come up in studies it is important that appropriate steps be made to correct them and prevent any errors or bias from entering the study.

Technical Abstract: The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up. The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower than expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues. The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power. Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.